Pharmaceutical composition containing pyridylaminoacetic acid compound

ABSTRACT

The purpose of the present invention is to provide a pharmaceutical composition that comprises a specific compound and exhibits a superior preservation efficacy, the specific compound being stable within the pharmaceutical composition, and to provide methods for improving the stability of the specific compound within the pharmaceutical composition and the preservation efficacy of the pharmaceutical composition. The pharmaceutical composition according to the present invention comprises isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof, and further comprises edetic acid or a salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.15/204,507, filed on Jul. 7, 2016, the entire contents which areincorporated herein by reference and priority to which is herebyclaimed. U.S. application Ser. No. 15/204,507 is a continuation under 35U.S.C. § 120 of PCT/JP2015/050334 filed on Jan. 8, 2015, which isincorporated herein reference and which claimed priority to JapaneseApplication No. 2014-002810, filed Jan. 10, 2014, the entire content ofwhich is also incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition comprisingisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof, and a method for stabilizing the compound or saltthereof.

BACKGROUND ART

Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateis a compound represented by the following formula (1):

Patent Document 1 and Patent Document 2 mention pyridylaminoacetic acidcompounds such as isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,and Patent Document 1 mentions, as eye drops of the pyridylaminoaceticacid compound, Formulation Examples comprising concentrated glycerol andPolysorbate 80.

However, there is not mentioned a pharmaceutical composition comprisingisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof, which further compriss edetic acid or a salt thereof,and also there is absolutely no mention that stability of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof in the pharmaceutical composition, and preservativeeffectiveness of the pharmaceutical composition are improved.

Patent Document 1: U.S. Published Patent Application Publication, No.2012/0190852, Specification

Patent Document 2: U.S. Published Patent Application Publication, No.2011/0054172, Specification

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

At a stage of development of a pharmaceutical composition comprisingisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof (hereinafter also referred to as “the presentcompound”), the present inventors have found that, in an aqueouscomposition comprising the present compound dissolved therein, stabilityof the present compound is inferior.

An object of the present invention is to provide a pharmaceuticalcomposition comprising the present compound, in which the presentcompound in the pharmaceutical composition is stable, the pharmaceuticalcomposition having excellent preservative effectiveness. Another objectof the present invention is to provide a method for improving stabilityof the present compound in the pharmaceutical composition, andpreservative effectiveness of the pharmaceutical composition.

Means for Solving the Problems

The present inventors have intensively studied about additives in thecomposition comprising the present compound so as to achieve the aboveobjects, and found that the present compound in a pharmaceuticalcomposition has a high remaining rate even under long-term storage whenfurther adding edetic acid or a salt thereof in the compositioncomprising the present compound, and that the pharmaceutical compositionhas excellent preservative effectiveness, thus completing the presentinvention. Namely, the present invention is related to the following.

-   -   (1) A pharmaceutical composition comprising isopropyl        (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate        or a salt thereof, which further compriss edetic acid or a salt        thereof.    -   (2) A pharmaceutical composition comprising isopropyl        (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate        or a salt thereof and a nonionic surfactant, which further        compriss edetic acid or a salt thereof.    -   (3) The pharmaceutical composition according to (2), wherein the        nonionic surfactant includes polyoxyethylene castor oil,        polyoxyethylene hardened castor oil, polyoxyethylene sorbitan        fatty acid ester, or vitamin E TPGS.    -   (4) The pharmaceutical composition according to (3), wherein the        polyoxyethylene castor oil includes polyoxyethylene castor oil        selected from the group consisting of polyoxyl 5 castor oil,        polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35        castor oil, and polyoxyl 40 castor oil.    -   (5) The pharmaceutical composition according to (3), wherein the        polyoxyethylene hardened castor oil includes polyoxyethylene        castor oil selected from the group consisting of polyoxyethylene        hardened castor oil 10, polyoxyethylene hardened castor oil 40,        polyoxyethylene hardened castor oil 50, and polyoxyethylene        hardened castor oil 60.    -   (6) The pharmaceutical composition according to (3), wherein the        polyoxyethylene sorbitan fatty acid ester includes        polyoxyethylene castor oil selected from the group consisting of        Polysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene        sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and        Polysorbate 65.    -   (7) The pharmaceutical composition according to any one of (2)        to (6), wherein the content of the nonionic surfactant is in a        range of 0.001 to 5% (w/v).    -   (8) The pharmaceutical composition according to (7), wherein the        content of the nonionic surfactant is in a range of 0.8 to 2%        (w/v).    -   (9) The pharmaceutical composition according to any one of (2)        to (8), wherein the content of the nonionic surfactant is in a        range of 1 to 20,000 parts by mass relative to 1 part by mass of        6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl        acetate or a salt thereof.    -   (10) The pharmaceutical composition according to any one of (1)        to (9), wherein the content of        6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl        acetate or a salt thereof is in a range of 0.0001 to 0.10%        (w/v).    -   (11) The pharmaceutical composition according to (10), wherein        the content of        6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl        acetate or a salt thereof is in a range of 0.001 to 0.003%        (w/v).    -   (12) The pharmaceutical composition according to any one of (1)        to (11), wherein the content of edetic acid or a salt thereof is        in a range of 0.001 to 1% (w/v).    -   (13) The pharmaceutical composition according to (12), wherein        the content of edetic acid or a salt thereof is in a range of        0.01 to 0.1% (w/v).    -   (14) The pharmaceutical composition according to any one of (1)        to (13), wherein the content of edetic acid or a salt thereof is        in a range of 0.1 to 1,000 parts by mass relative to 1 part by        mass of        6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl        acetate or a salt thereof.    -   (15) The pharmaceutical composition according to any one of (1)        to (14), which further comprises boric acid or a salt thereof,        citric acid or a salt thereof, or acetic acid or a salt thereof.    -   (16) The pharmaceutical composition according to any one of (1)        to (15), which does not comprise sorbic acid.    -   (17) The pharmaceutical composition according to any one of (1)        to (16), which is filled into a container made of polyethylene.    -   (18) The pharmaceutical composition according to any one of (1)        to (17), for prevention or treatment of glaucoma or ocular        hypertension, or for reduction of intraocular pressure.    -   (19) A method for stabilizing isopropyl        (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate        or a salt thereof by allowing a pharmaceutical composition        comprising isopropyl        (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate        or a salt thereof to comprise edetic acid or a salt thereof.    -   (20) A method for improving preservative effectiveness of a        pharmaceutical composition comprising isopropyl        (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate        or a salt thereof by allowing the pharmaceutical composition to        comprise edetic acid or a salt thereof.

The respective structures of the above-mentioned (1) to (20) can becombined by optionally selecting two or more structures therefrom.

Effects of the Invention

According to the present invention, it is possible to provide apharmaceutical composition in which the present compound in apharmaceutical composition is stabilized over a long period of time, thepharmaceutical composition having excellent preservative effectiveness.The pharmaceutical composition of the present invention has enoughsafety as a pharmaceutical product. According to the present invention,it is also possible to provide a method for stabilizing the presentcompound in a pharmaceutical composition over a long period of time tothereby improve preservative effectiveness of the pharmaceuticalcomposition. According to the present invention, it is also possible toprovide a method for using edetic acid or a salt thereof so as toproduce a pharmaceutical composition in which the present compound inthe pharmaceutical composition is stabilized over a long period of time,the pharmaceutical composition having excellent preservativeeffectiveness.

PREFERRED MODE FOR CARRYING OUT THE INVENTION

Embodiments of the present invention will be described in detail below.

It is possible to produce isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof comprised in a pharmaceutical composition of thepresent invention in accordance with a conventional method in thetechnical field, such as a method mentioned in U.S. Published PatentApplication Publication, No. 2012/0190852, Specification.

In the pharmaceutical composition of the present invention, a salt ofisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateis not particularly limited as long as it is a pharmacologicallyacceptable salt. Specifically, there are exemplified inorganic acidsalts such as hydrochlorides, hydrobromates, hydroiodides, nitrates,sulfates, or phosphates; or organic acid salts such as acetates,trifluoroacetates, benzoates, oxalates, malonates, succinates, maleates,fumarates, tartrates, citrates, methanesulfonates, ethanesulfonates,trifluoromethanesulfonates, benzenesulfonates, p-toluenesulfonates,glutamates, or aspartates. Preferably, hydrochlorides ortrifluoroacetates are exemplified.

In the pharmaceutical composition of the present invention, the contentof isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof is not particularly limited. Specifically, the lowerlimit is preferably 0.0001% (w/v), more preferably 0.0003% (w/v), stillmore preferably 0.0005% (w/v), and yet still more preferably 0.001%(w/v). The upper limit is preferably 0.1% (w/v), more preferably 0.03%(w/v), still more preferably 0.01% (w/v), yet still more preferably0.008% (w/v), even still more preferably 0.005% (w/v), and particularlypreferably 0.003% (w/v). More specifically, the content is preferably ina range of 0.0001 to 0.1% (w/v), more preferably 0.0003 to 0.03% (w/v),still more preferably 0.0005 to 0.01% (w/v), yet still more preferably0.001 to 0.008% (w/v), even still more preferably 0.001 to 0.005% (w/v),and most preferably 0.001 to 0.003% (w/v). Comparatively small contentof the present compound may enable a reduction in amount of a surfactant(typically polyoxyethylene castor oil), which is required to dissolvethe present compound, so that the content of the present compound ispreferably less than 0.01% (w/v). When comprising a salt of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,it means that the content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetatefalls in the above range in a state where the salt is isolated.

In the pharmaceutical composition of the present invention, it isdesired to mix surfactants so as to dissolve the present compound. It ispossible to appropriately mix a cationic surfactant, an anionicsurfactant, and a nonionic surfactant, which are usable as additives fora pharmaceutical product, in the pharmaceutical composition of thepresent invention as surfactants. Of these surfactants, a nonionicsurfactant is preferable.

Examples of the cationic surfactant include alkylamine salt,alkylaminepolyoxyethylene adduct, fatty acid triethanolamine monoestersalt, acylaminoethyldiethylamine salt, fatty acid polyamine condensate,alkyltrimethylammonium salt, dialkyldimethylammonium salt,alkyldimethylbenzylammonium salt, alkylpyridinium salt, acylaminoalkyltype ammonium salt, acylaminoalkylpyridinium salt,diacyloxyethylammonium salt, alkylimidazoline,1-acylaminoethyl-2-alkylimidazoline, 1-hydroxylethyl-2-alkylimidazoline,and the like. Examples of the alkyldimethylbenzylammonium salt includebenzalkonium chloride, cetalkonium chloride, and the like. Examples ofthe anionic surfactant include phospholipid, and the like; and examplesof the phospholipid include lecithin, and the like.

Examples of the nonionic surfactant include polyoxyethylene castor oil,polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acidester, Vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylenepolyoxypropylene glycol, sucrose fatty acid ester, and the like. Ofthese surfactants, polyoxyethylene castor oil is preferable from aviewpoint of being capable of further improving stability.

It is possible to use, as the polyoxyethylene castor oil, variouspolyoxyethylene castor oils each exhibiting different number ofpolymerization of ethylene oxide. The number of polymerization ofethylene oxide is preferably in a range of 5 to 100, more preferably 20to 50, particularly preferably 30 to 40, and most preferably 35.Specific examples of the polyoxyethylene castor oil include polyoxyl 5castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35castor oil, polyoxyl 40 castor oil, and the like, and polyoxyl 35 castoroil is most preferable.

It is possible to use, as the polyoxyethylene hardened castor oil,various polyoxyethylene hardened castor oils each exhibiting differentnumber of polymerization of ethylene oxide. The number of polymerizationof ethylene oxide is preferably in a range of 10 to 100, more preferably20 to 80, particularly preferably 40 to 70, and most preferably 60.Specific examples of the polyoxyethylene hardened castor oil includepolyoxyethylene hardened castor oil 10, polyoxyethylene hardened castoroil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardenedcastor oil 60, and the like, and polyoxyethylene hardened castor oil 60is most preferable.

Examples of the polyoxyethylene sorbitan fatty acid ester includePolysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan trioleate, Polysorbate 65, and thelike, and Polysorbate 80 is most preferable.

Vitamin E TPGS is also referred to as tocopherol polyethylene glycol1000 succinate ester.

Examples of the polyoxyethylene fatty acid ester include polyoxyl 40stearate, and the like.

Examples of the polyoxyethylene polyoxypropylene glycol includepolyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39)glycol, polyoxyethylene (196) polyoxypropylene (67) glycol,polyoxyethylene (20) polyoxypropylene (20) glycol, and the like.Examples of the sucrose fatty acid ester include sucrose stearic acidester, and the like.

In the pharmaceutical composition of the present invention, the contentof the surfactant is not particularly limited. Specifically, the lowerlimit is preferably 0.001% (w/v), more preferably 0.01% (w/v), stillmore preferably 0.1% (w/v), particularly preferably 0.5% (w/v), and mostpreferably 0.8% (w/v). The upper limit is preferably 10% (w/v), morepreferably 5% (w/v), still more preferably 4% (w/v), particularlypreferably 3% (w/v), and most preferably 2% (w/v). More specifically,the content is preferably in a range of 0.001 to 10% (w/v), morepreferably 0.01 to 5% (w/v), still more preferably 0.1 to 4% (w/v),particularly preferably 0.5 to 3% (w/v), and most preferably 0.8 to 2%(w/v). The above content is applied to any surfactant, and isparticularly preferably for a nonionic surfactant.

In the pharmaceutical composition of the present invention, the contentof the nonionic surfactant relative to6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof is not particularly limited. Specifically, thelower limit of the content of the nonionic surfactant is preferably 1part by mass, more preferably 10 parts by mass, still more preferably 50parts by mass, yet still more preferably 100 parts by mass, andparticularly preferably 200 parts by mass, relative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof. The upper limit is preferably 20,000 parts bymass, more preferably 10,000 parts by mass, still more preferably 5,000parts by mass, yet still more preferably 3,000 parts by mass, andparticularly preferably 2,000 parts by mass. More specifically, thecontent of the nonionic surfactant is preferably in a range of 1 to20,000 parts by mass, more preferably 10 to 10,000 parts by mass, stillmore preferably 50 to 5,000 parts by mass, particularly preferably 100to 3,000 parts by mass, and most preferably 200 to 2,000 parts by mass,relative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof.

In the pharmaceutical composition of the present invention, examples ofthe salt of edetic acid include monosodium edetate, disodium edetate,tetrasodium edetate, and the like.

In the pharmaceutical composition of the present invention, the contentof edetic acid or a salt thereof is not particularly limited.Specifically, the lower limit of the content is preferably 0.001% (w/v),more preferably 0.005% (w/v), still more preferably 0.01% (w/v), andmost preferably 0.02% (w/v). The upper limit of the content ispreferably 1.0% (w/v), more preferably 0.5% (w/v), still more preferably0.1% (w/v), and most preferably 0.05% (w/v). More specifically, thecontent of edetic acid or a salt thereof is preferably in a range of0.001 to 1% (w/v), more preferably 0.005 to 0.5% (w/v), and mostpreferably 0.01 to 0.1% (w/v).

In the pharmaceutical composition of the present invention, the contentof edetic acid or a salt thereof relative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof is not particularly limited. Specifically, thelower limit of the content of edetic acid or a salt thereof ispreferably 0. 1 part by mass, more preferably 0.2 part by mass, stillmore preferably 0.5 part by mass, particularly preferably 1 part bymass, and most preferably 3 parts by mass, relative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof. The upper limit is preferably 1,000 parts bymass, more preferably 500 parts by mass, still more preferably 200 partsby mass, particularly preferably 100 parts by mass, and most preferably50 parts by mass. More specifically, the content of edetic acid or asalt thereof is preferably in a range of 0.1 to 1,000 parts by mass,more preferably 0.2 to 500 parts by mass, still more preferably 0.5 to200 parts by mass, particularly preferably 1 to 100 parts by mass, andmost preferably 3 to 50 parts by mass, relative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof.

Additives can be optionally used in the pharmaceutical composition ofthe present invention, and it is possible to add, as additives, a bufferagent, a tonicity agent, a stabilizer, a preservative, an antioxidant, ahigh molecular weight polymer, and the like.

It is possible to mix the buffer agent, which is usable as additives fora pharmaceutical product, in the pharmaceutical composition of thepresent invention. Examples of the buffer agent include phosphoric acidor a salt thereof, boric acid or a salt thereof, citric acid or a saltthereof, acetic acid or a salt thereof, carbonic acid or a salt thereof,tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, andthe like. From a viewpoint of buffering capacity in a weak acid region,the buffer agent is preferably boric acid or a salt thereof, citric acidor a salt thereof, or acetic acid or a salt thereof, and particularlypreferably citric acid or a salt thereof. Examples of the phosphateinclude sodium phosphate, sodium dihydrogen phosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogen phosphate,dipotassium hydrogen phosphate, and the like; examples of the borateinclude borax, sodium borate, potassium borate, and the like; examplesof the citrate include sodium acetate, disodium citrate, trisodiumcitrate, and the like; examples of the acetate include sodium acetate,potassium acetate, and the like; examples of the carbonate includesodium carbonate, sodium hydrogen carbonate, and the like; and examplesof the tartrate include sodium tartrate, potassium tartrate, and thelike. When the buffer agent is mixed in the pharmaceutical compositionof the present invention, the content of the buffer agent can beappropriately adjusted according to the type of the buffer agent, and ispreferably in a range of 0.001 to 10% (w/v), more preferably 0.01 to 5%(w/v), still more preferably 0.1 to 3% (w/v), and most preferably 0.2 to2% (w/v).

It is possible to appropriately mix the tonicity agent, which is usableas additives for a pharmaceutical product, in the pharmaceuticalcomposition of the present invention. Examples of the tonicity agentinclude an ionic tonicity agent, a nonionic tonicity agent, and thelike. Examples of the ionic tonicity agent include sodium chloride,potassium chloride, calcium chloride, magnesium chloride, and the like;and examples of the nonionic tonicity agent include glycerol, propyleneglycol, sorbitol, mannitol, and the like. When the tonicity agent ismixed in the pharmaceutical composition of the present invention, thecontent of the tonicity agent can be appropriately adjusted according tothe type of the tonicity agent, and is preferably in a range of 0.01 to10% (w/v), more preferably 0.02 to 7% (w/v), still more preferably 0.1to 5% (w/v), particularly preferably 0.5 to 4% (w/v), and mostpreferably 0.8 to 3% (w/v).

It is possible to appropriately mix the stabilizer, which is usable asadditives for a pharmaceutical product, in the pharmaceuticalcomposition of the present invention. Examples of the stabilizer includesodium citrate, and the like. When the stabilizer is mixed in thepharmaceutical composition of the present invention, the content of thestabilizer can be appropriately adjusted according to the type of thestabilizer.

It is possible to appropriately mix the preservative, which is usable asadditives for a pharmaceutical product, in the pharmaceuticalcomposition of the present invention. Examples of the preservativeinclude benzalkonium chloride, benzalkonium bromide, benzethoniumchloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propylparaoxybenzoate, chlorobutanol, and the like. From a viewpoint ofstability of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof, it is desired not to include sorbic acid.When the preservative is mixed in the pharmaceutical composition of thepresent invention, the content of the preservative can be appropriatelyadjusted according to the type of the preservative, and is preferably ina range of 0.0001 to 1% (w/v), more preferably 0.0005 to 0.1% (w/v),still more preferably 0.001 to 0.05% (w/v), and most preferably 0.002 to0.01% (w/v).

It is possible to appropriately mix the antioxidant, which is usable asadditives for a pharmaceutical product, in the pharmaceuticalcomposition of the present invention. Examples of the antioxidantinclude ascorbic acid, tocopherol, dibutylhydroxytoluene,butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite,and the like. When the antioxidant is mixed in the pharmaceuticalcomposition of the present invention, the content of the antioxidant canbe appropriately adjusted according to the type of the antioxidant, andis preferably in a range of 0.0001 to 1% (w/v), more preferably 0.0005to 0.1% (w/v), still more preferably 0.001 to 0.02% (w/v), and mostpreferably 0.005 to 0.010% (w/v).

It is possible to appropriately mix the high molecular weight polymer,which is usable as additives for a pharmaceutical product, in thepharmaceutical composition of the present invention. Examples of thehigh molecular weight polymer include methyl cellulose, ethyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose, sodium carboxymethyl cellulose,hydroxypropylmethylcellulose acetate succinate,hydroxypropylmethylcellulose phthalate, carboxymethylethyl cellulose,cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol,carboxyvinyl polymer, polyethylene glycol, and the like. When the highmolecular weight polymer is mixed in the pharmaceutical composition ofthe present invention, the content of the high molecular weight polymercan be appropriately adjusted according to the type of the highmolecular weight polymer, and is preferably in a range of 0.001 to 5%(w/v), more preferably 0.01 to 1% (w/v), and still more preferably 0.1to 0.5% (w/v).

The pH of the pharmaceutical composition of the present invention ispreferably in a range of 4.0 to 8.0, more preferably 4.5 to 7.5, stillmore preferably 5.0 to 7.0, and most preferably 5.5 to 6.5.

The pharmaceutical composition of the present invention can be stored ina container made of various raw materials. For example, it is possibleto use containers made of polyethylene, polypropylene, and the like.From a viewpoint of ease of instillation (hardness of container) andstability of the present compound, it is preferred to store in acontainer made of polyethylene.

The dosage form of the pharmaceutical composition of the presentinvention is not particularly limited as long as it is usable as apharmaceutical product. Examples of the dosage form include eye drop,ophthalmic injection, and the like, and eye drop is particularlypreferable. They can be produced in accordance with a conventionalmethod in the technical field. The pharmaceutical composition of thepresent invention is basically a solution, and a solvent or dispersionmedium thereof is preferably water.

The pharmaceutical composition of the present invention is useful forprevention or treatment of glaucoma or ocular hypertension, or forreduction of intraocular pressure. Examples of glaucoma in the presentinvention include primary open-angle glaucoma, secondary open-angleglaucoma, normal tension glaucoma, hypersecretion glaucoma, primaryclosed-angle glaucoma, secondary closed-angle glaucoma, plateau irisglaucoma, mixed glaucoma, developmental glaucoma, steroid glaucoma,exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignantglaucoma, capsular glaucoma, plateau iris syndrome, and the like.

The pharmaceutical composition of the present invention may comprise oneor a plurality of, preferably 1 to 3 of, and more preferably one or twoother glaucoma or ocular hypertension therapeutic agent(s) orintraocular tension depressor(s). The other glaucoma therapeutic agentsis not particularly limited. Specifically, the other glaucomatherapeutic agent is preferably a commercially available glaucomatherapeutic agent or a glaucoma therapeutic agent under development,more preferably a commercially available glaucoma therapeutic agent, andparticularly preferably a commercially available glaucoma therapeuticagent whose mechanism of action is different from that of the presentcompound. More specifically, there are exemplified a non-selectivesympathomimetic agent, an α2 receptor agonist, an α1 receptorantagonist, a β receptor antagonist, a parasympatholytic agent, acarbonate dehydratase inhibitor, prostaglandins, a Rho kinase inhibitor,and the like.

Specific examples of the non-selective sympathomimetic agent includedipivefrin; specific examples of the α2 receptor agonist includebrimonidine and apraclonidine; specific examples of the α1 receptorantagonist include bunazosin; specific examples of the β receptorantagonist include timolol, befunolol, carteolol, nipradilol, betaxolol,levobunolol, and metipranolol; specific examples of theparasympatholytic agent include pilocarpine; specific examples of thecarbonate dehydratase inhibitor include dorzolamide, brinzolamide, andacetazolamide; specific examples of prostaglandins include latanoprost,isopropyl unoprostone, bimatoprost, and travoprost; and specificexamples of the Rho kinase inhibitor include ripasudil.

EXAMPLES

Formulation Examples and test results will be shown below, but such arefor better understanding of the present invention and do not limit thescope of the present invention.

Formulation Examples

Typical Formulation Examples using the present compound will be shownbelow. In the following Formulation Examples, the mixing amount of eachcomponent is the content in 100 mL of the composition.

Formulation Example 1

-   -   Eye drop (in 100 mL)    -   Present compound 0.001 g    -   Boric acid 0.2 g    -   Glycerol 2.0 g    -   Polysorbate 80 0.5 g    -   Disodium edetate 0.05 g    -   Benzalkonium chloride 0.005 g    -   Dilute hydrochloric acid q.s.    -   Sodium hydroxide q.s.    -   Purified water q.s.

Formulation Example 2

-   -   Eye drop (in 100 mL)    -   Present compound 0.001 g    -   Sodium dihydrogen phosphate 0.2 g    -   Glycerol 2.0 g    -   Vitamin E TPGS 0.8 g    -   Disodium edetate 0.05 g    -   Benzalkonium chloride 0.005 g    -   Dilute hydrochloric acid q.s.    -   Sodium hydroxide q.s.    -   Purified water q.s.

Formulation Example 3

-   -   Eye drop (in 100 mL)    -   Present compound 0.001 g    -   Trisodium citrate 0.2 g    -   Glycerol 2.0 g    -   Polyoxyethylene hardened castor oil 60 0.3 g    -   Disodium edetate 0.05 g    -   Benzalkonium chloride 0.005 g    -   Dilute hydrochloric acid q.s.    -   Sodium hydroxide q.s.    -   Purified water q.s.

Types and mixing amounts of the present compound, nonionic surfactant,edetic acid, and additives in Formulation Examples 1 to 3 can beappropriately adjusted to obtain desired compositions.

1. Stability Evaluation Test (1)

An influence of edetic acid on stability of the present compound wasstudied.

1-1. Preparation of Test Formulation

To 5 g of polyoxyl 35 castor oil, 20 mL of a 10% sodium dihydrogenphosphate solution, 10 mL of a 5% disodium edetate dihydrate solution,and 900 mL of purified water were added and dissolved. After adjustingthe pH to about 6 by adding a sodium hydroxide solution or dilutehydrochloric acid (q.s.), 0.003 g of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate(hereinafter also referred to as the compound A) was added anddissolved. To this was added purified water (q.s.) to make 1,000 mL intotal, thus preparing a formulation of Example 1.

In the same manner as in preparation method of Example 1, formulationsof Example 2 and Comparative Examples 1 to 2 shown in Table 1 wereprepared.

1-2. Test Procedure

After filling a glass ampule with 5 mL of a test formulation and storingat 60° C. for an optional period, the content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetatewas determined using high-performance liquid chromatography, and then aremaining rate (%) thereof was calculated.

1-3. Test Results and Consideration

Test results are shown in Table 1.

TABLE 1 Comparative Comparative % (w/v) Example 1 Example 2 Example 1Example 2 Present compound A 0.0003 0.0003 0.0003 0.0003 Disodiumedetate dihydrate 0.05 0.05 — — Polyoxyethylene hardened 0.5 — 0.5 —castor oil 60 Polysorbate 80 — 0.5 — 0.5 Sodium dihydrogen 0.2 0.2 0.20.2 phosphate HCl/NaOH q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s.q.s. pH 6.0 6.0 6.0 6.0 Remaining 60° C./1 Week 96.9 93.6 24.2 69.5rate(%)

As is apparent from Table 1, the formulations of Examples 1 to 2maintained significantly high remaining rate at 60° C. for a week, ascompared with the formulations of Comparative Examples 1 and 2. Theresults revealed that the pharmaceutical composition of the presentinvention has excellent stability.

2. Stability Evaluation Test (2)

An influence of additives and pH in the pharmaceutical composition ofthe present invention was studied.

2-1. Preparation of Test Formulation

In the same manner as in preparation method of Example 1, theformulations of Examples 3 to 34 shown in Tables 2 to 8 were prepared.

2-2. Test Procedure

After filling a glass ampule with 5 mL of a test formulation and storingat 60° C. for an optional period, the content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetatewas determined using high-performance liquid chromatography, and then aremaining rate (%) thereof was calculated.

TABLE 2 % (w/v) Example 3 Example 4 Example 5 Example 6 Example 7Present compound A 0.01 0.0003 0.001 0.01 0.03 Polyoxyl 35 castor oil0.8 0.5 0.8 2 2 Sodium dihydrogen 0.2 0.2 0.2 0.2 0.2 phosphate Disodiumedetate 0.01 0.05 0.05 0.05 0.05 dihydrate Glycerol 2.3 — 2.3 2.3 2.3Benzalkonium chloride 0.004 — 0.004 0.004 0.004 HCl/NaOH q.s. q.s. q.s.q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. pH 5.8 6.0 5.8 5.8 5.8Remaining 60° C./ 94.5 ND 93.02 94.0 94.1 rate(%) 1 Week 60° C./ 86.283.2 82.2 87.1 90.9 4 Weeks

TABLE 3 Example Example Example Example Example Example Example % (w/v)8 9 10 11 12 13 14 Present compound A 0.003 0.003 0.003 0.003 0.003 0.010.01 Polyoxyl 35 castor 0.8 0.8 0.8 0.8 0.8 0.8 0.8 oil Sodiumdihydrogen 0.2 — — — — — — phosphate Boric acid — 1 — — — 1 — Trisodium— — 0.2 — — — — citratedihydrate Sodium — — — 0.2 — — —acetatetrihydrate ϵ-Aminocaproic acid — — — — 0.2 — — Trometamol — — — —— — 0.9 Disodium edetate 0.02 0.02 0.02 0.02 0.02 0.05 0.05 dihydrateGlycerol 2.2 1.0 2.2 2.2 2.2 1.4 0.8 Benzalkonium 0.004 0.004 0.0040.004 0.004 0.004 0.004 chloride HCl/NaOH q.s. q.s. q.s. q.s. q.s. q.s.q.s. Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 6.0 6.0 6.06.0 6.0 5.8 5.8 Remaining 60° C./ rate(%) 2 Weeks 94.6 94.0 95.1 94.394.4 93.1 92.6

TABLE 4 % (w/v) Example 15 Example 16 Example 17 Example 18 Presentcompound A 0.01 0.01 0.01 0.01 Polyoxyl 35 castor oil 0.8 0.8 0.8 0.8Sodium dihydrogen phosphate 0.2 0.2 0.2 0.2 Disodium edetate dihydrate0.05 0.05 0.05 0.05 Glycerol 2.3 2.3 2.3 2.3 Benzalkonium chloride 0.0020.008 0.004 0.004 HCl/NaOH q.s. q.s. q.s. q.s. Purified water q.s. q.s.q.s. q.s. pH 5.8 5.8 5.0 6.5 Remaining 60° C./ 95.3 94.1 94.8 92.6rate(%) 2 Weeks

TABLE 5 Example Example Example Example % (w/v) 19 20 21 22 Presentcompound A 0.003 0.003 0.003 0.003 Polyoxyl 35 castor oil 0.8 0.8 0.80.8 Boric acid 1 1 — — ϵ-Aminocaproic acid — — 0.2 0.2 Disodium edetatedihydrate 0.02 0.02 0.02 0.02 Glycerol 1 — 2.3 — Mannitol — 2.0 — 4.5Benzalkonium chloride 0.0013 0.0013 0.0013 0.0013 HCl/NaOH q.s. q.s.q.s. q.s. Purified water q.s. q.s. q.s. q.s. pH 6.0 6.0 6.0 6.0Remaining 60° C./ 93.3 93.0 93.4 93.6 rate(%) 2 Weeks

TABLE 6 Example Example Example Example Example Example Example % (w/v)23 24 25 26 27 28 29 Present compound A 0.0003 0.0003 0.0003 0.00030.0003 0.003 0.0003 Polysorbate 80 0.5 0.5 0.5 0.5 0.5 0.8 — Vitamin ETPGS — — — — — — 0.5 Sodium dihydrogen 0.2 0.2 — — — — — phosphate Boricacid — — 1 — — — 1 Sodium — — — 1 — — — citratehydrate Trometamol — — —— 1 — — Trisodium 0.2 citratedihydrate Disodium edetate 0.05 0.05 0.050.05 0.05 0.02 0.01 dihydrate Sodium chloride 0.8 — — — — — — Glycerol —2.2 — — — 2.2 1.0 Benzalkonium — — — — — 0.004 0.01 chloride HCl/NaOHq.s. q.s. q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s.q.s. q.s. q.s. pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Remaining 60° C./ 93.895.3 96.0 93.7 96.1 94.0 86.0 rate(%) 2 Weeks

TABLE 7 % (w/v) Example 30 Example 31 Example 32 Present compound A0.0003 0.0003 0.0003 Polysorbate 80 0.5 0.8 0.8 ϵ-Aminocaproic acid 0.20.2 0.2 Disodium edetate dihydrate 0.02 0.02 0.02 Glycerol — 2.3 —Mannitol 4.5 — 4.5 Benzalkonium chloride 0.0013 0.0013 0.0013 HCl/NaOHq.s. q.s. q.s. Purified water q.s. q.s. q.s. pH 6.0 6.0 6.0 Remaining60° C./ 90.2 93.2 93.9 rate(%) 2 Weeks

TABLE 8 % (w/v) Example33 Example34 Present compoundA 0.0003 0.0003Polyoxyl 35 castor oil 0.8 0.8 Boric acid 1 1 Sorbic acid 0.1 — Disodiumedetate dihydrate 0.05 0.05 Glycerol 1 1 Benzalkonium chloride 0.01 0.01HCl/NaOH q.s. q.s. Purified water q.s. q.s. pH 6.5 6.5 Remaining rate(%)60° C./2 Weeks 89.1 92.5

As is apparent from Tables 2 to 8, the formulations of Examples 3 to 34maintained a high remaining rate at 60° C. over 2 or 4 weeks.

3. Preservative Effectiveness Evaluation Test

Preservative effectiveness of the pharmaceutical composition of thepresent invention was studied.

3-1. Preparation of Test Formulation

In the same manner as in preparation method of Example 1, theformulations of Examples 35 to 43 and Comparative Example 3 shown inTables 9 and 10 were prepared.

TABLE 9 % (w/v) Example35 Example36 Example37 Example38 Example39Present compound A 0.003 0.0003 0.003 0.003 0.003 Polyoxyl 35 castor oil0.8 0.8 0.8 0.2 0.8 Boric acid 1.0 1.0 1.0 1.0 1.0 Disodium edetate0.005 0.02 0.05 0.01 0.01 dihydrate Glycerol 1.0 1.0 1.0 1.0 1.0Benzalkonium chloride 0.0085 0.0085 0.0085 0.004 0.0085 HCl/NaOH q.s.q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. pH 5.5 5.55.5 5.0 6.5

TABLE 10 Example Example Example Example Comparative % (w/v) 40 41 42 43Example 3 Present compound A 0.003 0.0003 0.001 0.003 0.003 Polyoxyl 35castor oil 0.8 0.8 1.4 — 0.8 Polysorbate 80 — — — 0.8 — Trisodium 0.20.2 0.14 0.2 — citratedihydrate Citric acidmonohydrtae — — 0.03 — —Boric acid — — — — 1.0 Disodium edetate 0.02 0.02 0.02 0.02 — dihydrateGlycerol 2.2 2.2 2.3 2.2 1.0 Benzalkonium chloride 0.0085 0.004 0.00850.004 0.0085 HCl/NaOH q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s.q.s. q.s. q.s. pH 6.0 6.0 5.6 6.0 5.5

3-2. Test Procedure Bacterial Strains

The following strains were used as inoculum.

Bacteria

Escherichia coli, Escherichia Coli ATCC 8739

Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 9027

Staphylococcus aureus, Staphylococcus aureus ATCC 6538

Yeast Fungus and Molds

Candida albicans, Candida albicans ATCC 10231

Aspergillus niger, Aspergillus niger ATCC 16404

Test Procedure

A test was performed in accordance with a preservative effectivenesstest defined in Sixteenth Revised Japanese Pharmacopoeia. Namely, aninoculum solution was prepared so as to adjust the concentration in arange of 107 to 108 cfu/mL and each formulation of Examples 35 to 43 andComparative Example 3 was aseptically inoculated with each inoculumsolution so as to adjust the concentration in a range of 105 to 106cfu/mL, followed by uniform mixing to give samples. These samples werestored under light-shielded condition at 20 to 25° C. and, after 14 and28 days, 1 mL of each sample was collected and the number of generalviable bacteria was measured.

The number of general viable bacteria of bacteria, yeast fungus, andmolds was measured in accordance with a most probable number methoddefined in a microbial limit test of Sixteenth Revised JapanesePharmacopoeia.

From the number of general viable bacteria determined by the mostprobable number method, a remaining rate was determined on theassumption that an initial bacterial count determined from the inoculumsolution is 100.

Judging Method

The case where the number of general viable bacteria after 14 and 28days satisfies criteria of Table 11 in all bacterial strains was judgedas “Passed”. When all results in each sampling are judged as “Passed”,it was judged that “preservative effectiveness exists”.

TABLE 11 Sampling time Bacteria Yeast fungus and molds After 14 days0.1% or less relative to Same level as that of inoculumnumberinoculumnumber or less After 28 days Same level as that of Same level asthat of inoculumnumber or less after 14 inoculumnumber or less days

3-3. Test Results and Consideration

Test results and judgements are shown in Table 12.

TABLE 12 Results and judgments of preservative effectiveness testBacterial strains After 14 days After 28 days Judgment Example 35Bacteria Passed Passed Preservative Yeast fungus and Passed Passedeffectiveness molds exists Example 36 Bacteria Passed PassedPreservative Yeast fungus and Passed Passed effectiveness molds existsExample 37 Bacteria Passed Passed Preservative Yeast fungus and PassedPassed effectiveness molds exists Example 38 Bacteria Passed PassedPreservative Yeast fungus and Passed Passed effectiveness molds existsExample 39 Bacteria Passed Passed Preservative Yeast fungus and PassedPassed effectiveness molds exists Example 40 Bacteria Passed PassedPreservative Yeast fungus and Passed Passed effectiveness molds existsExample 41 Bacteria Passed Passed Preservative Yeast fungus and PassedPassed effectiveness molds exists Example 42 Bacteria Passed PassedPreservative Yeast fungus and Passed Passed effectiveness molds existsExample 43 Bacteria Passed Passed Preservative Yeast fungus and PassedPassed effectiveness molds exists Comparative Bacteria Not Passed PassedNo preservative Example 3 Yeast fungus and Passed Passed effectivenessmolds exists

As is apparent from Table 12, the formulations of Examples 35 to 43 havepreservative effectiveness which conforms to standards of a preservativeeffectiveness test defined in Sixteenth Revised Japanese Pharmacopoeia.These results revealed that the pharmaceutical composition of thepresent invention has excellent preservative effectiveness.

1. A pharmaceutical composition comprising isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof, which further comprises edetic acid or a saltthereof.
 2. A pharmaceutical composition comprising isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof and a nonionic surfactant, which further comprisesedetic acid or a salt thereof.
 3. The pharmaceutical compositionaccording to claim 2, wherein the nonionic surfactant includespolyoxyethylene castor oil, polyoxyethylene hardened castor oil,polyoxyethylene sorbitan fatty acid ester, or vitamin E TPGS.
 4. Thepharmaceutical composition according to claim 3, wherein thepolyoxyethylene castor oil includes polyoxyethylene castor oil selectedfrom the group consisting of polyoxyl 5 castor oil, polyoxyl 9 castoroil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40castor oil.
 5. The pharmaceutical composition according to claim 3,wherein the polyoxyethylene hardened castor oil includes polyoxyethylenecastor oil selected from the group consisting of polyoxyethylenehardened castor oil 10, polyoxyethylene hardened castor oil 40,polyoxyethylene hardened castor oil 50, and polyoxyethylene hardenedcastor oil
 60. 6. The pharmaceutical composition according to claim 3,wherein the polyoxyethylene sorbitan fatty acid ester includespolyoxyethylene castor oil selected from the group consisting ofPolysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan trioleate, and Polysorbate
 65. 7.The pharmaceutical composition according to claim 2, wherein the contentof the nonionic surfactant is in a range of 0.001 to 5% (w/v).
 8. Thepharmaceutical composition according to claim 7, wherein the content ofthe nonionic surfactant is in a range of 0.8 to 2% (w/v).
 9. Thepharmaceutical composition according to claim 2, wherein the content ofthe nonionic surfactant is in a range of 1 to 20,000 parts by massrelative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof.
 10. The pharmaceutical composition accordingto claim 1, wherein the content of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-yl)sulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof is in a range of 0.0001 to 0.1% (w/v).
 11. Thepharmaceutical composition according to claim 10, wherein the content of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-sulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof is in a range of 0.001 to 0.003% (w/v). 12.The pharmaceutical composition according to claim 1, wherein the contentof edetic acid or a salt thereof is in a range of 0.001 to 1% (w/v). 13.The pharmaceutical composition according to claim 12, wherein thecontent of edetic acid or a salt thereof is in a range of 0.01 to 0.1%(w/v).
 14. The pharmaceutical composition according to claim 1, whereinthe content of edetic acid or a salt thereof is in a range of 0.1 to1,000 parts by mass relative to 1 part by mass of6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropylacetate or a salt thereof.
 15. The pharmaceutical composition accordingto claim 1, which further compriss boric acid or a salt thereof, citricacid or a salt thereof, or acetic acid or a salt thereof.
 16. Thepharmaceutical composition according to claim 1, which does not comprisesorbic acid.
 17. The pharmaceutical composition according to claim 1,which is filled into a container made of polyethylene.
 18. Thepharmaceutical composition according to claim 1, for prevention ortreatment of glaucoma or ocular hypertension, or for reduction ofintraocular pressure.
 19. A method for stabilizing isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof by allowing a pharmaceutical composition comprisingisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof to comprise edetic acid or a salt thereof.
 20. Amethod for improving preservative effectiveness of a pharmaceuticalcomposition comprising isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof by allowing the pharmaceutical composition to compriseedetic acid or a salt thereof.